Phylogenetic relationships among organisms have been demonstrated many times, and studies from a diversity of prokaryotic and eukaryotic organisms suggest a more or less gradual evolution of biochemical and physiological mechanisms and metabolic pathways. Despite different evolutionary pressures, proteins that regulate the cell cycle in yeast, nematode, fly, rat, and man have common chemical or structural features and modulate the same general cellular activity. Comparisons of human gene sequences with those from other organisms where the structure and/or function may be known allow researchers to draw analogies and to develop model systems for testing hypotheses. These model systems are of great importance in developing and testing diagnostic and therapeutic agents for human conditions, diseases and disorders.
Signal transduction cascades alter gene expression by activation or suppression of transcription factor activity. Two basic types of transcription factors exist within the cell. Steroid hormone receptors are transcription factors whose activity is regulated by binding to lipid soluble hormones, such as steroids, retinoids, and thyroid hormones. Nuclear receptors are transcription factors, such as CREB (cAMP-response element binding protein), STAT (Signal Transducers and Activators of Transcription),and the TCF (ternary complex factor)-SRF (serum-response factor) complex, whose activity is regulated by phosphorylation cycles. The kinases and phosphatases that regulate the phosphorylation cycle respond to extracellular signals, such as growth factors and cytokines.
Hormone binding or phosphorylation induce conformational changes in transcription factors which promote their association with a diverse group of nuclear transcription factor binding proteins (TFBPs) including steroid receptor co-activator (SRC)-1, transcriptional intermediary factor (TIF), and CREB binding protein (CBP)/p300. These TFBPs function as modulators of transcription and show specificity towards transcription factor and associated ligands. For example, PIAS (protein inhibitor of activated STAT)-3 preferentially binds phosphorylated Stat3. Furthermore, IL-6 but not interferon-.gamma. stimulates interaction between Stat3 and PIAS3 (Chung et al. (1997) Science 278:1803-1805). Many TFBPs also have a restricted tissue distribution. For example, .beta.-3 adrenergic agonists activate peroxisome proliferator-activated receptor (PPAR)-.gamma.. PPAR.gamma. is a major regulator of fat cell-specific gene regulation and differentiation, but does not inherently distinguish whether fat cells proceed along energy storage (white fat) or energy dissipation (brown fat) pathways. PGC-1, a modulator of PPAR.gamma., is found only in brown fat and leads to specific activation of genes associated with energy dissipating adaptive thermogenesis (Puigserver et al. (1998) Cell 92:829-839).
A short sequence motif LXXLL is necessary and sufficient to mediate binding of TFBPs to activated nuclear receptors (Heery et al. (1997) Nature 387:733-736). The motif forms an .alpha.-helix and occurs at the boundary of nuclear receptor interaction domains. ARIP3, which contains two LXXLL motifs, is an androgen receptor binding protein expressed predominantly in the testis which provides tissue specific gene activation by androgens (Moilanen et al. (1999) J. Biol. Chem. 274:3700-3704). ARIP3 is a member of a family of related TFBPs which include the PIAS proteins and Gu/RNA helicase II-binding protein (GBP). These proteins show 60-80% homology over the N-terminal and central regions of the proteins, but contain divergent C-termini. All of the PIAS family members also contain a potential zinc finger motif which is involved in transcription factor binding.
TFBPs, by binding and modulating transcription factor activity in a signal and tissue specific manner, provide additional regulation to cell signaling events. Inappropriate expression or activation of TFBPs can alter gene expression patterns and cell fates. AIB (amplified in breast cancer)-1, a member of the SRC1 family, interacts with the estrogen receptor and enhances estrogen receptor-dependent gene transcription. It is ubiquitously expressed in normal human tissues and is amplified and overexpressed in many breast and ovarian cancer cell lines and in breast cancer tumor samples (Anzick et al. (1997) Science 277:965-968). Mice lacking brown fat develop severe obesity and insulin resistance. Chronic exposure to .beta.-3 adrenergic agonists cause brown fat hypertrophy and thermogenic, anti-obesity effects due to enhanced activity of PGC1-PPAR.gamma. (Puigserver, supra).
The discovery of a polynucleotide encoding a new mammalian protein satisfies a need in the art by providing new compositions which are useful in the characterization, diagnosis, prevention, and treatment of cell proliferative disorders.